3.4. Effects of Defective TFIIH on Carcinogenesis and Cancer Treatment
As TFIIH plays a critical role in maintaining genome stability, cells with defective TFIIH are more likely to have high genome instability, which may further elevate cancer risk. Indeed, somatic mutations in the XPD gene, which is also named ERCC2, have been widely observed in tumors, such as bladder and urothelial cancers (Kim et al., 2016). Tumors of the urothelial tract and bladder are associated with exposure to tobacco and other DNA damaging chemicals that induce bulky lesions (Freedman et al., 2011; Ploeg et al., 2009). Lack of TFIIH may render the exposed cells more vulnerable to these damaging agents, thereby promoting genome instability and tumor growth. Additionally, it has been shown that somatic mutations in XPD are associated with a distinct genomic signature in urothelial tumors, signature 5*, which closely resembles COSMIC signature 5 (Kim et al., 2016). There is also evidence indicating a correlation between signature 5* and smoking (Kim et al., 2016), which suggests that low repair of tobacco-induced DNA damage in XPD-mutated cancer cells may drive this unique mutation signature. On the other hand, somatic mutations in XPD also represent an intrinsic vulnerability of the tumor cells to various therapies. This idea has been tested in bladder cancer, in which XPD somatic mutations are frequently found. The published data shows that many clinically observed XPD mutations enhance sensitivity to cisplatin in cancer cell lines and mouse xenograft models (Q. Li et al., 2019).
Another common mutation site is in the CDK7 subunit of the CAK complex of TFIIH. Mutations in this subunit are associated with triple negative breast cancer, peripheral T-cell lymphomas, and ovarian cancer. Preclinical models have shown that the use of CDK7 inhibitors reduces drug resistance in human cells and mouse models (Rimel & Taatjes, 2018).